Abstract
Aspartate semialdehyde dehydrogenase (ASADH) functions at a critical junction in the aspartate-biosynthetic pathway and represents a valid target for antimicrobial drug design. This enzyme catalyzes the NADPH-dependent reductive dephosphorylation of β-aspartyl phosphate to produce the key intermediate aspartate semialdehyde. Production of this intermediate represents the first committed step in the biosynthesis of the essential amino acids methionine, isoleucine and threonine in fungi, and also the amino acid lysine in bacteria. The structure of a new fungal form of ASADH from Cryptococcus neoformans has been determined to 2.6 Å resolution. The overall structure of CnASADH is similar to those of its bacterial orthologs, but with some critical differences both in biological assembly and in secondary-structural features that can potentially be exploited for the development of species-selective drugs.